Although survival rates for children diagnosed with a primary malignant brain tumor have improved, radiation induced damage to the developing nervous system remains a significant problem. Few treatment options are available once malignant cells have metastasized to the leptomeninges that surround the brain and spinal cord. Leptomeningeal metastasis (LM) cannot be surgically resected, and systemic chemotherapy is hindered by the presence of the blood-brain and blood-spinal cord barriers, leaving high dose craniospinal radiation as the only effective treatment option. Some investigators have administered therapeutics directly into the intrathecal space with the hope that locally administered drugs will better reach LM. However, action of intrathecally administered agents is limited by rapid clearance and inadequate tissue penetration as cerebrospinal fluid (CSF) turns over. Furthermore, most traditional chemotherapeutics are poorly water soluble and cannot be administered to the CSF at relevant concentrations. We have recently developed a novel approach for encapsulating the histone deacetyle inhibitor (HDACI) quisinostat within biodegradable and biocompatible NPs (QNPs). Our preliminary data demonstrate that intrathecally administered NPs distribute readily across the surfaces of the brain and spinal cord, are well retained within the subarachnoid space, and localize with lesions to slow the growth of LM in a murine model of metastatic medulloblastoma. Here, we propose a comprehensive approach for optimizing the design of radiation sensitizing NPs for intrathecal drug delivery to treat LM. These NPs serve not just as a stationary depot to prolong drug presence in the central nervous system but as mobile carriers that we predict will selectively sensitize metastatic lesions to radiation. We will, (1) engineer the surface of NPs to further improve their localization with LM, (2), determine the relationship between drug delivery and efficacy in models of medulloblastoma, and, (3), establish species scaling of direct-to-CSF nanoparticle delivery. Treatments will be evaluated in patient derived and genetically engineered models of medulloblastoma exhibiting LM. Fluorescent barcoding, matrix assisted laser desorption ionization (MALDI), and positron emission tomography (PET) imaging approaches will be used to precisely localize NP and drug delivery to LM with quantitative, cellular-level resolution. By directly pairing multiple measures of delivery, activity, and efficacy, we expect to develop a comprehensive understanding of barriers to effective drug delivery within the subarachnoid space. Most importantly, these studies will advance new nanotechnology toward the clinic for better treatment of pediatric brain tumors.